Geralyn Spollett, MSN, C-ANP, CDE,1 and Carol Brunzell, RDN, LD, CDE2
1Spollett is an adult nurse practitioner at Yale Diabetes Center, New Haven, CT. 2Brunzell is a registered dietitian nutritionist and certified diabetes educator at M Health, University of Minnesota Physicians in Minneapolis, MN.
Cystic fibrosis (CF), one of the most common lethal genetic diseases in Caucasians, affects >30,000 children and adults in the U.S., with 1,000 children diagnosed each year. It is a progressive disease causing lung infections with limited ability to breathe over time. The disease has no cure, but with advances in research and treatment, people with CF are living longer. The median predicted survival for people with CF has increased by 8 years since 2002, from 31.3 years in 2002 to 39.3 years in 2014; however, many people live into their sixth and seventh decades.1 With the increase in survival, the number of patients with CF-related diabetes (CFRD) also has risen, becoming a leading comorbidity in this group. CFRD occurs in ~20% of adolescents and 40–50% of adults, but it can occur at any age and is associated with worse survival. Impaired glucose tolerance (IGT) occurs in up to 75% of adults with CF.2–4
CFRD is a distinct clinical entity. It shares components of both type 1 diabetes (T1D) and type 2 diabetes (T2D). It differs, however, from both T1D and T2D in that it is characterized by insulinopenia, but periods of insulin resistance also occur as a result of stress, pregnancy, illness, and use of steroids for pulmonary exacerbations. Ketoacidosis is extremely rare because of residual endogenous insulin secretion.4 As with T2D, the onset is often insidious and can exist for 2–4 years before diagnosis. The initial deficiency is an impaired first-phase insulin response; as patients age, peak insulin response is delayed and less robust than normal.5
In CF, abnormal glucose tolerance is associated with progressive clinical deterioration.6 Research has shown that the rate of pulmonary decline is directly proportional to the magnitude of abnormal glucose tolerance and the degree of insulin deficiency.6 Survival rates for patients with CFRD have improved over the years, and early diagnosis and treatment through aggressive screening have been shown to improve overall health, nutritional status, lung function, and survival.3
CF affects the tissues that produce mucus secretions and alters the properties of that mucus so that it is no longer a protective substance but rather an obstructive, damaging one. Excessive, thick, sticky mucus blocks the airways, sinuses, the gastrointestinal tract, the ducts of the pancreas, the bile ducts of the liver, and the male urogenital tract.
Chemical changes in the mucus proteins increase the viscosity and provide an environment ideal for bacterial growth. White blood cells are released to combat the infection but only result in complicating the problem. Genetic materials from dying white blood cells increase the stickiness of the mucus and initiate a cycle of further obstruction, infection, and inflammation.
The thick, sticky secretions can clog the pancreatic ducts, damaging the pancreas in a variety of ways. A reduction in the amounts of pancreatic enzymes and bicarbonate alter the digestive and absorptive process. This insufficiency can result in malnutrition and slowed growth and development. Stools become bulky and foul smelling. Eventually, blockage of the pancreatic ducts damages the β-cells, resulting in hyperglycemia. Fibrosis and scarring disrupt the architecture of the islet cell and cause islet cell destruction. Glucagon and pancreatic polypeptide secretion are reduced. Proinsulin levels are elevated, and first-phase insulin and C-peptide secretion in response to glucose are impaired. This impairment results in delayed and diminished insulin secretion in response to oral intake or glucose.2 This progression to CFRD cannot be prevented.
The pathophysiological changes associated with CF affect glucose metabolism. Malabsorption and abnormal intestinal transit time, glucagon deficiency, liver dysfunction, and increased caloric needs to prevent malnutrition disrupt glucose control. Systemic inflammatory processes, chronic and acute infections, and the use of steroids commonly given to treat the inflammation increase insulin resistance and cause further deterioration in glucose stability. Patients with CFRD are not at risk for macrovascular disease despite the need to eat high-fat, high-sodium diets. Thus far, no patient with CF has been reported to have died from atherosclerotic cardiovascular disease.7,8 Patients with CFRD are at risk for the development of microvascular diseases: retinopathy, neuropathy, and nephropathy. This development of microvascular disease is related to the duration and metabolic control of diabetes.9–11
SUMMARY OF RECOMMENDATIONS FOR THE CLINICAL CARE OF CFRD
In 2009, the CFRD Consensus Conference committee convened to update its evidence-based recommendations for the screening, diagnosis, and management of CFRD using the American Diabetes Association (the Association) and U.S. Preventive Services Task Force grading systems.12
Screening for CFRD
Undetected CFRD causes deterioration in pulmonary and nutritional status, resulting in increased mortality. Because CFRD can be clinically silent, the CFRD Consensus Committee recommends annual screening starting at the age of 10 years in those with CF. The use of A1C as a screening test is not recommended because the results can be falsely low in this population. Rather, a 2-h 75-g oral glucose tolerance test (OGTT) has been shown to be the most sensitive measure to detect CFRD and is the screening test of choice.12
The most common age of onset is 18–21 years. Diabetes screening also should be done whenever symptoms suggestive of hyperglycemia are present, including polydipsia, polyuria, weight loss, alterations in growth patterns or puberty progression, unexplained pulmonary function decline, or increased infections. During steroid therapy or at the onset of pregnancy or pulmonary exacerbations, cautious monitoring for diabetes symptoms should be increased (see Table 33.1).
Table 33.1—Screening Recommendations
1. The use of A1C as a screening test for CFRD is not recommended. (ADA-B; USPSTF-D)
2. Screening for CFRD should be performed using a 2-h 75-g OGTT. (ADA-E; Consensus)
3. Annual screening for CFRD should begin by age 10 years in all CF patient s who do not have CFRD. (ADA B; USPSTF-B)
4. CF patients with acute pulmonary exacerbation requiring intravenous antibiotics and/or systemic glucocorticoids should be screened for CFRD by monitoring fasting and 2-h postprandial plasma glucose levels for the first 48 h. If elevated blood glucose levels are found by SMBG, the results must be confirmed by a certified laboratory. (ADA-E; Consensus)
5. Screening for CFRD by measuring mid- and immediate postfeeding plasma glucose levels is recommended for CF patients on continuous enteral feedings, at the time of gastrostomy feeding initiation and then monthly by SMBG. Elevated glucose levels detected by SMBG must be confirmed by a certified laboratory. (ADA-E; Consensus)
6. Women with CF who are planning a pregnancy or confirmed pregnant should be screened for preexisting CFRD with a 2-h 75-g fasting OGTT if they have not had a normal CFRD screen in the last 6 months. (ADA-E; Consensus)
7. Screening for gestational diabetes mellitus is recommended at both 12–16 weeks’ and 24–28 weeks’ gestation in pregnant women with CF not known to have CFRD, using a 2-h 75-g OGTT with blood glucose measures at 0, 1, and 2 h. (ADA-E; Consensus)
8. Screening for CFRD using a 2-h 75-g fasting OGTT is recommended 6–12 weeks after the end of the pregnancy in women with gestational diabetes mellitus (diabetes first diagnosed during pregnancy). (ADA-E; Consensus)
9. CF patients not known to have diabetes who are undergoing any transplantation procedure should be screened preoperatively by OGTT if they have not had CFRD screening in the last 6 months. Plasma glucose levels should be monitored closely in the perioperative critical care period and until hospital discharge. Screening guidelines for patients who do not meet diagnostic criteria for CFRD at the time of hospital discharge are the same as for other CF patients. (ADA-E; Consensus)
Source: Adapted from Diabetes Care 2010;33: 2697–2708.
Diagnosis of CFRD
Diagnosis of CFRD can be made using the Association’s standard criteria when patients are in their usual baseline state of health. An elevated A1C may indicate the presence of hyperglycemia, but a normal A1C value does not exclude the diagnosis of diabetes. The rapid turnover rate of red blood cells in CF patients makes diagnosis through the A1C test unreliable. CFRD diagnosis also can be made during acute illness or enteral continuous drip feedings. The diagnosis of gestational diabetes mellitus should be made according to the recommendations of the International Association of the Diabetes and Pregnancy Study Groups using a 75-g OGTT. The 2009 CFRD Consensus Committee no longer distinguishes CFRD with or without fasting hyperglycemia (see Table 33.2).
Table 33.2—Diagnosis Recommendations
1. During a period of stable baseline health the diagnosis of CFRD can be made in CF patients according to standard ADA criteria. Testing should be done on 2 separate days to rule out laboratory error unless there are unequivocal symptoms of hyperglycemia (polyuria and polydipsia); a positive FPG or A1C can be used as a confirmatory test, but if it is normal the OGTT should be performed or repeated. If the diagnosis of diabetes is not confirmed, the patient resumes routine annual testing. (ADA-E; Consensus)
—2-h OGTT plasma glucose _200 mg/dl (11.1 mmol/l)
—FPG _126 mg/dl (7.0 mmol/l)
—A1C _ 6.5% (A1C _6.5% does not rule out CFRD because this value is often spuriously low in CF.)
—Classical symptoms of diabetes (polyuria and polydipsia) in the presence of a casual glucose level _200 mg/dl (11.1 mmol/l)
2. The diagnosis of CFRD can be made in CF patients with acute illness (intravenous antibiotics in the hospital or at home, systemic glucocorticoid therapy) when FPG levels _126 mg/dl (7.0 mmol/l) or 2-h postprandial plasma glucose levels _200 mg/dl (11.1 mmol/l) persist for more than 48 h. (ADA-E; Consensus)
3. The diagnosis of CFRD can be made in CF patients on enteral continuous drip feedings when mid- or postfeeding plasma glucose levels exceed 200 mg/dl (11.1 mmol/l) on 2 separate days. (ADA-E; Consensus)
4. Diagnosis of gestational diabetes mellitus should be made based on the recommendations of the IADPSG where diabetes is diagnosed based on 0-, 1-, and 2-h glucose levels with a 75-g OGTT if any one of the following is present:
—FPG _92 mg/dl (5.1 mmol/l)
—1-h plasma glucose _180 mg/dl (10.0 mmol/l)
—2-h plasma glucose _153 mg/dl (8.5 mmol/l) (ADA-E; Consensus)
CF patients with gestational diabetes mellitus are not considered to have CFRD, but require CFRD screening 6–12 weeks after the end of the pregnancy. (ADA-E; Consensus)
5. Distinguishing between CFRD with and without FH is not necessary. (ADA-B, USPSTF-D)
6. The onset of CFRD should be defined as the date a person with CF first meets diagnostic criteria, even if hyperglycemia subsequently abates. (ADA-E; Consensus)
Source: Adapted from Diabetes Care 2010;33: 2697–2708.
Management of CFRD
In general, insulin is the treatment of choice for CFRD. Depending on the level of β-cell impairment, bolus meal coverage with rapid-acting insulin may be all that is required initially.13 Carbohydrate counting and the use of an insulin-to-carbohydrate ratio system can provide the flexible coverage needed in CFRD. Because undernutrition secondary to high energy requirements is a major problem in CF, attaining and maintaining a healthy weight is critical for these patients; therefore, caloric, fat, sodium, and carbohydrate restrictions seen in the treatment of diabetes are not part of the care regimen.
Basal insulin, such as an evening dose of an intermediate-acting insulin or a long-acting insulin, frequently is needed to achieve euglycemic levels and improve nutritional status.14 Insulin pump therapy is another option and offers the patient more flexibility in dietary intake and can improve glucose management.15
The use of oral agents is not recommended in the treatment of CFRD. Metformin and the thiazolidinediones rely on clearance mechanisms that are compromised in CF. The increased potential for liver toxicity with thiazolidinediones in CF restricts their use. α-Glucosidase inhibitors affect intestinal absorption patterns in an already altered gastrointestinal tract. The side effects of the α-glucosidase inhibitors, such as nausea, flatulence, and diarrhea, may negatively affect the nutritional status of these patients. Sulfonylureas have been used but also are problematic. Higher rates of hypoglycemia have been observed before achievement of therapeutic glycemic ranges. Glyburide, 50% of which is eliminated in the bile, is not recommended because of the difficulty in drug excretion through bile ducts clogged as a result of CF (see Table 33.3).13,16
Table 33.3—Management Recommendations
1. Patients with CFRD should ideally be seen quarterly by a specialized multidisciplinary team with expertise in diabetes and CF. (ADA-E;Consensus)
2. Patients with CFRD should receive ongoing diabetes self-management education from diabetes education programs that meet national standards for DSME. (ADA-E; Consensus)
3. Patients with CFRD should be treated with insulin therapy. (ADA-A; USPSTF-B)
4. Oral diabetes agents are not as effective as insulin in improving nutritional and metabolic outcomes in CFRD and are not recommended outside the context of clinical research trials. (ADA-A; USPSTF-D)
5. Patients with CFRD who are on insulin should perform SMBG at least three times a day. (ADA-E; Consensus)
6. Patients with CFRD should strive to attain plasma glucose goals as per the ADA recommendations for all people with diabetes, bearing in mind that higher or lower goals may be indicated for some patients and that individualization is important. (ADA-E; Consensus)
7. A1C measurement is recommended quarterly for patients with CFRD. (ADA-E; Consensus)
8. For many patients with CFRD, A1C treatment goal is _7%, bearing in mind that higher or lower goals may be indicated for some patients and that individualization is important. (ADA-B; USPSTF-B)
9. CFF evidence-based guidelines for nutritional management are recommended for patients with CFRD. (ADA-E; Consensus)
10. Patients with CFRD should be advised to do moderate aerobic exercise for at least 150 min per week. (ADA-E; Consensus)
Source: Adapted from Diabetes Care 2010;33: 2697–2708.
All patients with CFRD should be seen by a specialized multidisciplinary team with expertise in diabetes and CF on a quarterly basis. Blood glucose targets are the same as for all other forms of diabetes and follow the recommendations set forth by the Association’s CRFD clinical guidelines.12 A1C testing and self-monitoring of blood glucose are prescribed based on management strategies and also are used to adjust therapy.
COMPLICATIONS OF CFRD
Patients with CFRD are living longer. Microvascular complications, such as retinopathy and nephropathy, have been reported in CFRD and appear to be related to duration of disease and level of glycemic control. Therefore, annual retinopathy and microalbumin screenings should be initiated at diagnosis.12 Patients with CFRD are usually thin and have normal lipid and blood pressure levels, reducing the risks of macrovascular complications. Annual monitoring for complications of diabetes is recommended starting 5 years after diagnosis of CFRD (see Table 33.4).
Table 33.4—Diabetes Complications Recommendations
1. Education about the symptoms, prevention, and treatment of hypoglycemia, including the use of glucagon, is recommended for patients with CFRD and their care partners. (ADA-E; Consensus)
2. Patients with CFRD should have their blood pressure measured at every routine diabetes visit as per ADA guidelines. Patients found to have systolic blood pressure _130 mmHg or diastolic blood pressure _80 mmHg or _90th percentile for age and sex for pediatric patients should have repeat measurement on a separate day to confirm a diagnosis of hypertension. (ADA-E; consensus)
3. Annual monitoring for microvascular complications of diabetes is recommended using ADA guidelines, beginning 5 years after the diagnosis of CFRD or, if the exact time of diagnosis is not known, at the time that FH is first diagnosed. (ADA-E; Consensus)
4. Patients with CFRD diagnosed with hypertension or microvascular complications should receive treatment as recommended by ADA for all people with diabetes, except that there is no restriction of sodium and, in general, no protein restriction. (ADA-E; Consensus)
5. An annual lipid profile is recommended for patients with CFRD and pancreatic exocrine sufficiency or if any of the following risk factors are present: obesity, family history of coronary artery disease, or immunosuppressive therapy following transplantation. (ADA-E; Consensus)
Source: Adapted from Diabetes Care 2010;33: 2697–2708.
Nutrition and CFRD
Achieving adequate nutrition intake for the increased metabolic needs of the person with CF and supporting the use of these calories through a matched insulin regimen is necessary for the health and survival of these patients. Patients with CFRD need to follow their usual high-calorie, high-fat, high-sodium diet. Protein intake should be ~15–20% of the daily diet. Fat and sodium restrictions usually prescribed for individuals with diabetes are not appropriate for patients with CFRD. These patients frequently are depleted of sodium and may require supplementation. Despite the use of pancreatic enzymes, fat malabsorption is a common component of the clinical picture. Caloric needs take precedence, with the current fat recommendation being 40% of total calories per day.17
Nutrition and Impaired Glucose Tolerance
For individuals with CF and impaired glucose tolerance (IGT), the usual recommendations for increased exercise and weight loss to address glucose intolerance are not implemented because they can adversely affect health status. Medical nutrition therapy focuses on healthy eating in the context of the usual high-calorie, high-fat, and high-sodium diet for CF and meal or snack timing. Glucose levels are maintained through a regulation of meal timing to spread carbohydrates and calories throughout the day, thus reducing glucose excursions. Reducing consumption of regular sodas or other sweetened beverages may help control glucose excursions. Food substitutions for any alteration in caloric level must be made to avoid weight loss. Helping the patient choose more nutritious replacements for the sweetened beverages is essential for the treatment of both diabetes and IGT. Exercise, although helpful for CF patients, should not be used as a weight-loss mechanism. Individuals who choose to exercise need to replace spent calories to avoid a negative energy balance. Insulin therapy becomes necessary if nutritional status changes and weight no longer is maintained or if pulmonary function declines.12 Yearly screening with an OGTT and self-monitoring of blood glucose performed during periods of infection and stress are necessary to therapeutically respond to glucose alterations.
Nutrition and Pregnancy in CF
Preconception and pregnancy care in CFRD follow the standard guidelines for glucose control. Adequate weight gain takes on more significance in light of the nutritional needs of pregnancy and the caloric needs of CF. Referral to a registered dietitian is imperative for counseling and education to achieve positive outcomes. As with all diabetes-affected pregnancies, insulin requirements will change, and the patient will need to remain in close contact with her health-care providers. Alterations in pulmonary function and its effect on both glucose control and fetal health, however, make good communication among all members of the health-care team vital. Table 33.5 outlines medical nutrition therapy recommendations for CFRD compared with T1D and T2D and for pregnancy in CF and illustrates the differences in nutrition therapy.
Table 33.5—Nutrition Recommendations for Cystic Fibrosis–Related Diabetes Compared to Nutrition Recommendations for Type 1 and Type 2 Diabetes
Adequate nutritional status and blood glucose control are important components of therapy in all individuals with diabetes. In people with CFRD, however, the consequences of not meeting these basic requirements of diabetes care are life-threatening. Coordination of care between the diabetes and CF health-care teams is imperative for positive outcomes. Patient education and support in managing two serious chronic diseases will help the patient maintain function and increase longevity. Without proper glycemic control, the patient’s nutritional status declines and weight loss occurs. Assisting the patient in analyzing glucose levels and injecting the appropriate amount of premeal insulin requires an understanding of food and insulin action. Diabetes education plays a vital role in the health maintenance of people with CFRD. Education literature is available from the Association and the Cystic Fibrosis Foundation. The Cystic Fibrosis Foundation’s website (www.cff.org) is accessible to help both patients and health-care providers remain current on CF treatment protocols and lifestyle interventions.
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